tbuckley/cabot-search huggingface dataset:
A phase I/II study to evaluate the safety, pharmacodynamics, and efficacy of entinostat in combination with atezolizumab and bevacizumab in patients with renal cell carcinoma.
Authors: Roberto Pili, Naomi B. Haas, Paul Monk, Theodore F. Logan, Vivek Narayan, Heather Burney, Nabil Adra
Journal: Journal of Clinical Oncology (2023)

4526 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may enhance or resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we conducted a Phase I/II clinical study with the HDAC inhibitor entinostat in combination with the immune check point inhibitor atezolizumab and the VEGF inhibitor bevacizumab in RCC pts, either treatment naïve or previously treated with immune checkpoint inhibitors. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a Phase I/II clinical trial. This clinical study was composed of a Dose Finding Phase (Phase I) and a two-stage Phase (Phase II) portion. Due to unforeseen circumstances, enrollment was halted during Stage I of the Phase II portion. In the Phase I dose finding cohorts, according to the 3+3 standard design, pts received oral entinostat at 1 mg (dose level or dl1), 3 mg (dl 2), or 5 mg (dl 3) every 7 days, continuously, with atezolizumab at a dose of 1,200 mg/kg mg IV every three weeks in combination with bevacizumab at a dose of 15 mg/kg IV every 3 weeks. Phase II patients were split into two distinct cohorts: Cohort A (no prior treatments with PD-1 or PD-L1 inhibitors) and Cohort B (at least one prior treatment with a PD-1 or PD-L1 inhibitor for metastatic disease). Pts treated at dl3 were included in the Phase II efficacy analyses. Results: 31 pts (18 and 13 pts during Phase I and II, respectively) were enrolled. Phase I was completed with the following DLTs: hypertension (3) in dl1, encephalopathy and hyponatremia (dl2), pneumonitis and pruritis (dl3). Dl3 was established as the recommended phase II dose. The most common treatment-related toxicities were thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. A total of 21 grade≥3 events were observed. Nine pts achieved a partial response in Cohort A and one patient in Cohort B with an ORR 60% (CI 32.3-83.7) and 33.3% (28.2-56.4), respectively. According to Simon’s optimal two-stage design, the ORR met the Stage I primary objective. The median PFS was 13.7 months (CI 8.7-21.3) in Cohort A and 9.8 months (CI 1.3-NE) in Cohort B. We have collected blood samples to conduct several correlative studies on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and atezolizumab plus bevacizumab is relatively well tolerated and may be active in pts with ccRCC. Clinical trial information: NCT03024437 .
Phase 3 PANOVA-3 study: Tumor treating fields (TTFields) therapy concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer.
Authors: Hani M. Babiker, Teresa Macarulla, Philip Agop Philip, Carlos Roberto Becerra, Tomislav Dragovich, Vincent J. Picozzi
Journal: Journal of Clinical Oncology (2023)

TPS4199 Background: Tumor Treating Fields (TTFields) therapy is a locoregional antimitotic treatment approved for newly diagnosed and recurrent glioblastoma GBM and pleural mesothelioma. TTFields (150 kHz) therapy, with/without chemotherapy, had antiproliferative and anticlonogenic activity in pancreatic cancer cell lines, and reduced tumor volume and weight more than chemotherapy alone in in vivo models. TTFields therapy with gemcitabine and nab-paclitaxel (GnP) was well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC) in the phase 2 PANOVA study (NCT01971281). LAPC prognosis remains poor despite available therapies, which can negatively impact quality of life (QoL). As such, there remains a need for effective and tolerable treatments. Methods: PANOVA-3 (EF-27, NCT03377491) is a prospective, randomized, phase 3 study investigating the efficacy and safety of TTFields therapy with GnP in patients with LAPC, with a planned enrollment of 556 patients. Key inclusion criteria are: a diagnosis of unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment. Patients will be stratified by performance status and geographical region and assigned 1:1 to treatment groups to receive TTFields therapy + GnP or GnP alone. GnP will be administered at a standard dose per standard of care. TTFields therapy (150 kHz, 18h/day) will be delivered by the NovoTTF-200T System until local disease progression per RECIST v1.1. Usage will be tracked by the device. Follow-up will be performed every 4 weeks and computed tomography scans of the chest and abdomen will be taken every 8 weeks until disease progression. Patients will be followed every month until death. The primary endpoint is overall survival and key secondary endpoints include QoL, pain-free survival, and puncture-free survival, which will be compared between treatment groups. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Guidance around usage, lifestyle integration and prevention and management of skin adverse events will be provided by Device Support Specialists and field personnel. Usage information will be provided to patients and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches aim to optimize patient usage and outcomes. The trial is currently recruiting at 149 sites, globally. The DMC last reviewed the trial in August 2022, and suggested that the trial continue as planned. Clinical trial information: NCT03377491 .
A novel three-biomarker signature (CA-62, CEA, CYFRA 21-1) and early-stage NSC lung cancer detection.
Authors: Janneta Tcherkassova, Sergei Tsurkan, Anna Prostyakova, Evgueni Klinski, Marina Sekacheva, Alexander Boroda, Ricardo Moro, David Berz
Journal: Journal of Clinical Oncology (2023)

3038 Background: A double-blind clinical study was conducted on 304 clinically verified blood serum samples, including 141 non-small cell lung cancer (NSCLC), 133 healthy volunteers and 30 patients with chronic obstructive pulmonary disease (COPD). The objectives of the study were: The assessment of various cancer markers and their possible combinations for detection of early (I-II) stages of non-small cell lung cancer (NSCLC) and evaluation of the best cancer markers panel as a pre-screening tool for NSCLC before Low-Dose CT scan. Methods: Quantitative measurement of various tumor markers for serum samples was carried out using electrochemiluminescent immunoassays Elecsys CA-125, ELECSYS CA 19-9, ELECSYS CYFRA 21-1 and ELECSYS SCC (COBAS, Roche Diagnostics GmbH, Germany, EU), enzyme immunoassay CA15-3-ELISA-BEST, CEA-ELISA-BEST, NSE-ELISA-BEST (JSC "VECTOR-BEST", RF) and immunochemiluminescent analysis CLIA-CA-62 (LLC "JVS Diagnostics", RF). The results were compared to the literature data for other biomarkers and their panels. Results: Unlike other tumor markers, which are expressed proportionally to tumor size, the marker for epithelial carcinomas CA-62 is expressed from Stage I and demonstrated the highest diagnostic results in detecting early stages (I-II) of NSCLC. The biomarkers CYFRA 21-1 and SCC do not have sufficient sensitivity and specificity to diagnose asymptomatic lung cancer. However, the addition of cytokeratin 19 CYFRA 21-1 to glycoproteins CA-62 and CEA increases the specificity by eliminating false positive results, which significantly improves the diagnostic value of the cancer marker signature (CA-62, CEA and CYFRA 21-1): 100% Specificity, 93% Sensitivity, 100% PPV, 94% NPV and 94% test accuracy. Conclusions: The results of the study demonstrated that using the biomarkers signature (CA-62, CEA and CYFRA 21-1) allows increasing the specificity of CT scan for patients with suspicious abnormalities on the tomogram, improving the interpretation of visualized localized lesion, and improving the accuracy of differential diagnosis at detecting early stages of LC up to 94%. In the prospective, adding cancer markers panel signature (CA-62, CEA and CYFRA 21-1) to the current lung cancer risk assessment system as a pre-screening tool for LDCT may improve the quality of early-stage Lung cancer detection by significant increasing the sensitivity and by reducing the proportion of false positive results. [Table: see text]
Development and validation of a clinical prognostic model for BRAF V600E mutated colorectal cancer patients based on pathological stage, microsatellite status, and primary tumor site.
Authors: Kai Ou, Lin Yang
Journal: Journal of Clinical Oncology (2023)

e15660 Background: Colorectal cancer patients with BRAF V600E mutations may be a heterogeneous population with different outcomes. Clinical and molecular pathologic factors related to the prognosis of colorectal cancer need further investigation. Methods: The clinical and pathological information of 206 patients with BRAF V600E mutated colorectal cancer diagnosed in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from 2014 to 2021 was retrospectively collected. LASSO regression, COX regression and Nomograms were used to develop clinical prognostic models. The differentiation was measured by C-statistic and decision curve analysis, and the predicted variability was evaluated by calibration curve. The prognostic model was externally validated with validation set data from 164 patients pooled from 5 studies. Results: Our clinical prognostic model included three variables: pathological stage, microsatellite status, and primary tumor site. In internal validation, the model had a concordant index of 0.785 (95%CI [0.732-0.839]) and a concordant index of 0.754 (95%CI [0.698-0.810]) using pathological staging. External validation confirmed the robustness of the model with a consistency index of 0.670 (95%CI ([0.617-0.724]) and a consistency index of 0.584 (95%CI [0.546-0.622]) using pathological staging. The application of decision curve analysis in both the training set and the validation set showed that our three-factor clinical prediction model was superior to the pathological staging. The calibration graph drawn based on the prediction and the actual situation is close to the 45° diagonal. Conclusions: By adding microsatellite status and primary tumor site on the basis of pathological stage, we improved the discriminability and prediction accuracy of the model, and successfully established a prognosis model for patients with BRAF V600E mutation of colorectal cancer.
Does non-alcoholic fatty liver disease (NAFLD) influence outcomes of pancreatic cancer (PANC)? A nationwide analysis.
Authors: Sriram Basappa Chowdary, Lekha Yadukumar, Udit Asija, Amit Munshi Sharma, Namita Sharma
Journal: Journal of Clinical Oncology (2023)

e16319 Background: Incidence of pancreatic cancer is 13.3 per 100,000 in the US, with a five-year survival rate of 11%. Studies worldwide have shown inconsistent positive associations between NAFLD and PANC in the general population. We aimed to assess the impact of NAFLD on trends of hospitalizations and outcomes of patients presenting with PANC in the US. Methods: We conducted a retrospective study from 2016 to 2020 using the National Inpatient Sample to identify PANC-related hospitalizations using ICD 10 codes. Population was divided based on the presence and absence of NAFLD. Pearson chi-square test and t-test were utilized. Primary outcome was in-hospital mortality. Secondary outcomes of hospitalization characteristics and comorbidities were compared. Multivariate analysis was used to adjust for confounders. Results: Out of the 4,34,160 hospitalizations with primary diagnosis of PANC, 1.43% of patients were found to have NAFLD. PANC with NAFLD cohort were younger with mean age 64.34 +/- 10.78 (vs. 68 +/-11.39). Females were common in the NAFLD group (56% vs. 48%). Caucasians were predominantly affected in both study groups. Patients with NAFLD had higher comorbidities such as diabetes (45.6% vs. 40%) and dyslipidemia (41.5% vs. 37%). Charlson's comorbidity index was &gt; 3 in the entire population with NAFLD compared to 85% in the group without NAFLD. Mortality was lower in patients with NAFLD (5.22 vs. 7.51). NAFLD did not lead to poor survival outcomes in pancreatic cancer patients with an Odds ratio of 0.31 (95% CI 0.24 - 0.41, p-value &lt;0.01). NAFLD patients had higher mean length of stay of 6.42 days (6.09-6.75) and were likely to incur higher hospitalization charges of $21,924 ($20,594 - $23,253). Conclusions: Patients with NAFLD presenting with PANC were younger, predominantly females, and had a marginally longer length of stay and healthcare utilization. NAFLD did not impact the mortality in patients hospitalized for PANC. [Table: see text]
Temporal trends in small cell lung cancer: Analysis of the U.S. Surveillance, Epidemiology and End Results (SEER) database.
Authors: Sean Cohen, Ben Brennan, Mousumi Banerjee, Gregory Peter Kalemkerian
Journal: Journal of Clinical Oncology (2023)

e20641 Background: Prior studies reported that the incidence of small cell lung cancer (SCLC) had decreased, while overall survival (OS) had improved, from 1973-2002. In 2019, immunotherapy was integrated into the standard therapy for patients with extensive-stage (ES) SCLC based on studies demonstrating an improvement in OS. This study aims to provide an update on SCLC incidence and survival at the dawn of this new therapeutic age. Methods: We analyzed data on all patients with primary lung cancer in the SEER17 database from 2000-2019. Patients with ICD-O codes 8002 and 8041-8044 were classified as SCLC. Incidence rates were calculated based on the standard U.S. population. OS was calculated based on censored time to death or last follow-up, whichever occurred earlier. Temporal trends in incidence and OS were evaluated using the Mantel-Haenszel chi-square statistic. Results: Of 847,747 patients with primary lung cancer, 111,263 (13.1%) had SCLC. The incidence rate of SCLC steadily declined from 8.8/100,000 in 2000 to 4.8/100,000 in 2019. Over this time, the incidence rate decreased among both males (10.7 to 5.1/100,000) and females (7.5 to 4.6/100,000), and among all examined races (NHW: 10.1 to 6.0/100,000, NHB: 8.3 to 4.7/100,000, NHA/PI: 3.5 to 1.6/100,000, Hispanic: 4.0 to 1.9/100,000). The proportional incidence of SCLC relative to NSCLC also continued to decline, from 14.5% in 2000 to 11.8% in 2019. The male:female ratio of SCLC patients decreased from 1.14:1 in 2000 to 0.93:1 in 2019. The percentage of patients with limited-stage (LS) SCLC decreased from 31.1% in 2000 to 26.4% in 2019. The majority of patients with LS-SCLC were female throughout the study period (53.9%), while most of those with ES-SCLC were male (51.8%). Among patients with LS-SCLC, 2-year OS increased from 26.7% in 2000 to 36.7% in 2017, while 5-year OS increased from 11.3% in 2000 to 15.6% in 2014. Among patients with ES-SCLC, 2-year OS increased from 6.4% in 2000 to 8.4% in 2017, while 5-year OS increased from 2.2% in 2000 to 2.9% in 2014. Both 2-year and 5-year OS increased in LS-SCLC over the study period in both males and females (M: 2-year: 23.4% to 36.2%, 5-year: 9.9% to 15.2%; F: 2-year: 29.9% to 37%, 5-year: 12.8% to 16.0%). In ES-SCLC, 2-year OS increased in both males and females (M: 5.8% to 7.3%, F: 7.0% to 9.5%), while 5-year OS increased in females (2.2% in 2000 to 3.9% in 2014), but remained stable in males (2.3% in 2000 to 2.0% in 2014). Conclusions: Both the incidence and proportional incidence of SCLC have continued to decline in the U.S. over the past 20 years. The male:female ratio also declined, with women now accounting for the majority of patients with SCLC. The percentage of patients with LS-SCLC decreased, likely due to improvements in staging procedures. Overall survival has continued to improve, with greater gains seen in LS-SCLC than in ES-SCLC prior to the integration of immunotherapy.
Using next-generation sequencing for RET fusion detection in Chinese cancer patients.
Authors: Huashao Dang, Phuong Anh Nguyen Thi, Zhentian Kai, Hongsheng He, Peng Luo
Journal: Journal of Clinical Oncology (2023)

e20516 Background: Approval Selpercatinib of FDA for lung and thyroid cancer patients harboured RET mutations or fusions attracts the investigation RET fusion partners and their ability for RET‐based targeted therapy. Here, we presented a genomic characteristics of RET fusion in six cancer type among 24,087 Chinese cancer patients. Methods: Tumor samples (including tissues, formalin-fixed paraffin-embedded or plasma) obtained from patients between March 2021 and February 2023 were used for RET fusion detection. Customed probes were designed to covered all exonic and intronic regions of 6, 10 and 11 for RET. GeneFuse and Delly softwares were used for analyzing RET fusion. To ensure both sensitivity and accuracy of fusion calling, RET fusions were only reported to fuse with a set of 600 cancer-related genes and require at least two individual supporting reads. Results: A total of 233 cases with RET fusion was identified among 24,087 patients with the given six cancer types including lung cancer, thyroid cancer, coloretal cancer, pancreatic cancer, oesophageal cancer and cancer of unknown primary site. A total of 6 fusion patterns were identified in the study cohort with KIF5B, CCDC6, NCOA4 and ERC1 being the most common RET fusion partners. Notably, two novel fusion partners (i.e. GOPC and VCL) were first reported in this study. RET variants frequencies were the highest in thyroid carcinoma (13/210, 6.19%), lung cancer (212/20,402; 1.04%), esophageal cancer (1/156, 0.64%), cancer of unknown primary site (2/374, 0.53%) , pancreatic cancer (1/337, 0.29%) and colorectal cancer (5/2,608, 0.19%). The results of the analysis revealed that different tumor types tend to have preferred fusion partners. For instance, KIF5B is highly specific in lung cancer, account for 72% of cases. Meanwhile, CCDC6 and NCOA4 are both enriched in thyroid cancer (both 46%). NCOA4 also present frequently in colorectal cancer, with 80% of cases displaying this partner. Conclusions: Detection of co‐occurrence of partner and RET fusions provide a guide to clinicians in deciding tumors as candidates for RET targeted therapies.
Impact of postoperative residual disease in patients with primary epithelial ovarian cancer in the era of maintenance therapies with targeted agents: A systematic review and meta-analysis.
Authors: Ji Hyun Kim, Se Ik Kim, Eun Young Park, Hyeong In Ha, Jae-Weon Kim, Robert L. Coleman, Robert E. Bristow, Sang-Yoon Park, Christina Fotopoulou, Myong Cheol Lim
Journal: Journal of Clinical Oncology (2023)

e17555 Background: To investigate the impact of residual disease after cytoreductive surgery for epithelial ovarian cancer (EOC) on survival outcomes in the era of targeted maintenance approaches, including bevacizumab and poly (ADP-ribose) polymerase (PARP) inhibitor administration. Methods: We searched relevant literature from the MEDLINE, Embase, and Cochrane Library databases to identify randomized controlled trials and prospective clinical trials of primary EOC published between 1 January 2000 and 22 September 2022. To evaluate the impact of postoperative residual tumors on PFS and OS, we constructed a linear regression model for log-transformed median progression-free survival (PFS) and overall survival (OS). Patients with and without first-line maintenance therapy were examined. The protocol was registered in the PROSPERO (CRD42021265810). Results: In total, 97 trials with 41,799 patients were included: 2476 received PARP inhibitors, and 6920 received bevacizumab. The median rate of complete cytoreduction was 36.3% (range, 0–99.4%), regardless of the timing of surgery. Multivariable analysis of the linear regression model of all studies revealed that the median OS increased by 12.97% for every 10% increase in complete cytoreduction rates, independently of the use of systemic maintenance. In subgroup analysis of patients with maintenance therapies, the effect of complete tumor clearance was potentiated, with a median OS increased by 19.13% for every 10% increase in complete cytoreduction rates. The previously described significant effect of total macroscopic tumor clearance of PFS could not be retained when adjusting for maintenance treatment. Conclusions: Total macroscopic tumor clearance at the initial presentation of EOC significantly prolongs OS. Our results establish the importance of complete surgical cytoreduction in the era of novel targeted systemic agents.
Multi-cancer brain metastasis risk score development and validation using 220,246 whole transcriptomes and machine learning.
Authors: Jim Abraham, Carey K. Anders, Adam Brufsky, Michael J. Glantz, Priscilla Kaliopi Brastianos, Luke Roy George Pike, Amy B. Heimberger, George W. Sledge, Matthew James Oberley, David Spetzler
Journal: Journal of Clinical Oncology (2023)

2039 Background: Brain metastases occur in multiple cancer types with higher prevalence in lung, breast, melanoma, and GI cancers. The prognoses of patients who develop brain metastases are very poor and identification of brain metastasis risk could be useful for prognostication, monitoring, and therapy selection. Methods: Data from the whole transcriptome of 220,246 tumor profiles were analyzed and multiple machine learning models were trained on various molecular subtypes. The dataset was split 50% for training and the other 50% for testing, UMAP was employed for dimensionality reduction and the patterns learned across the entirety of the training dataset irrespective of brain metastasis were leveraged on the testing data set. Patients with brain metastasis were identified using the presence of ICD-10 code C79.31 (Secondary malignant neoplasm of the brain). As the absence of C79.31 could be due to the event not happening yet, patients without brain metastasis were stratified into groups based on 3, 4 or greater than 5 years without a C79.31 ICD-10 code. The brain metastasis risk score was defined by empirical evaluation of the positive predictive value in 7 groups of risk probabilities. The validation set contained 1,217 patients with brain metastasis and 4,631 without an observed brain metastasis within 3 years. Results: In the validation set, the prevalence of brain metastases within the risk scores across all cancer types ranged from 4% with the lowest risk score to 94% in the highest with 71% of cases receiving the lowest 2 risk scores, 15% the 2 intermediate risk scores, and 14% the 3 highest risk scores. For breast, lung and colon cancers, the prevalence of brain metastasis ranged from 4-10% in patients with the lowest risk scores to 92-100% in patients with the highest however the distribution of cases with each risk score was markedly different across cancer type. Breast cancer had 62% of cases receiving the lowest 2 risk scores versus 27% in lung, and 92% in colon. Breast cancer had 18% of cases receiving the 3 highest risk scores while lung had 42% and colon only 2% of cases with those 3 highest scores. Conclusions: Whole transcriptome data can be leveraged by a machine learning platform that employs dimensionality reduction techniques along with transfer learning to predict the risk of brain metastasis. This tool can be used to augment the clinical picture of cancer patients an unmet clinical opportunity to inform prognosis, monitoring, and therapeutic selection.